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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:548.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis

Liam R. Brunham; Roshni R. Singaraja; MyNgan Duong; Jenelle M. Timmins; Catherine Fievet; Nagat Bissada; Martin H. Kang; Amrit Samra; Jean-Charles Fruchart; Bruce McManus; Bart Staels; John S. Parks; Michael R. Hayden

From the Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute (L.R.B., R.R.S., N.B., M.H.K., M.R.H.), University of British Columbia, Vancouver, Canada; the Department of Pathology/Section on Lipid Sciences (M.D., J.M.T., J.S.P.), Wake Forest University Health Sciences, Winston-Salem, NC; Institut Pasteur de Lille, Inserm U545 (C.F., J.C.F., B.S.), Université de Lille, France; and the iCAPTURE Centre (A.S., B.M.), St Paul’s Hospital/Providence Health Care, University of British Columbia, Vancouver, Canada.

Correspondence to Dr Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, Canada, V5Z 4H4. E-mail mrh{at}cmmt.ubc.ca

Objective— The ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial.

Methods and Results— We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1-containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr^–/– background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1. Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe^–/– background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr^–/– background displayed no change in atherosclerotic lesion area.

Conclusions— These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis.

We investigated the role of ABCA1 in atherosclerosis. Global ABCA1 overexpression reduced atherosclerosis. Deletion of hepatic Abca1 significantly accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, macrophage-specific inactivation of Abca1 displayed no change in atherosclerosis.

Key Words: lipid and lipoprotein metabolism • genetically altered mice • pathophysiology of atherosclerosis